1. Field of the Invention
The present invention relates to a method and apparatus for non-invasively measuring a blood sugar level on an in vivo and in situ basis using spectroscopic techniques. More specifically, the invention relates to a method and apparatus for non-invasively measuring the concentration of glucose in the blood stream or tissue of a patient suspected of suffering from diabetes based on a combination of wavelength modulation and intensity modulation of light.
2. Description of the Related Art
Various methods and apparatus for measuring the concentration of glucose in vitro and in vivo using spectroscopic techniques have been proposed.
For example, International application No. WO 81/00,622 discloses a method and apparatus for measuring the absorption of infrared light by glucose in body fluid using CO.sub.2 laser light as an irradiation light source. The method and apparatus measure the absorption spectra of serum and urine by transmittance and reflectance, i.e.--back scattering effects, at different wavelengths .lambda..sub.1 and .lambda..sub.2. Here, .lambda..sub.2 is a characteristic absorption wavelength of the substance to be measured, e.g. glucose, and .lambda..sub.1 is a wavelength at which absorption is independent of the concentration of the substance to be measured. The measurements are obtained by calculating the ratio of the absorbance at .lambda..sub.1 to the absorbance at .lambda..sub.2. The absorption band of the substance to be measured is between 940 cm.sup.-1 : and 950 cm.sup.-1 ; ie. between 10.64 and 10.54 .mu.m for wavelength .lambda..sub.1, and the absorption band is between 1090 cm.sup.-1 ; and 1095 cm.sup.-1 ; i.e.--between 9.17 .mu.m and 9.13 .mu.m for wavelength .lambda..sub.2.
U.S. Pat. No. 4,169,676 discloses an non-invasive examining method for detecting biological substances through skin using an attenuated-total-reflectance (ATR) prism. The method attaches the wave guide (ATR prism) directly to the surface of a sample under examination (e.g. a lip or tongue) and guides in infrared light. The refractive index of the wave guide is greater than that of the sample medium, ie. an optically thin layer of the surface, and the infrared light is made to pass through the prism along the total-reflection path. The infrared light interacts with the thin layer of the surface, and the interaction is related to the frustrated attenuation component of the light at the reflecting part (see Hormone & Metabolic Res. Suppl. Ser. (1979) pp. 30- 35). If infrared light of a wavelength related to the absorption of glucose is used, then the light passing through the prism is attenuated depending on the concentration of glucose in the optically thin layer of the surface. Therefore, the attenuated quantity is detected and processed into data on the glucose concentration.
U.S. Pat. No. 3,958,560 discloses a non-invasive detection apparatus that detects glucose in a patient's eye. Specifically, the apparatus of this U.S. patent is a sensor apparatus in shape of a contact lens comprising a light source that applies infrared light to one side of cornea and a detector that detects the transmitted light on the opposite side. When infrared light is applied to a measured location, the infrared light passes through the cornea and the aqueous humor and reaches the detector. The detector converts the quantity of transmitted light into an electric signal and provides it to a remote receiver. Then the reader of the receiver outputs the concentration of glucose in the patient's eye as a function of the individual change of quantity in the applied infrared light passing through the eye.
British Pat. application No. 2,035,557 discloses a detecting apparatus for assessing substances near the blood stream of a patient such as CO.sub.2, oxygen, or glucose. The detecting apparatus comprises an optical source and an optical receiving means that detects attenuated light back-scattered or reflected from inside a patient's body, i.e.--from the hypoderma, and uses ultraviolet or infrared light as the irradiation light.
On the other hand, there are following apparatus that measure or monitor the flow of blood and organism-activating parameters or components such as oxygenated hemoglobin and reduced oxyhemoglobin.
U.S. Pat. No. 3,638,640 discloses a method and apparatus for measuring oxygen and other substances in blood and the tissue. The U.S. Pat. apparatus comprises an irradiation light source and a detector placed on a patient's body. If the detector is placed on an ear, then the intensity of light passing through the ear is measured, and if the detector is placed on a forehead, then the intensity of light reflected after passing through blood and the hypoderma is measured. The wavelengths between red light and near-infrared light are used as the irradiation light, i.e.--660 nm, 715 nm, and 805 nm. The number of wavelengths used at the same time is 1 plus the number of wavelengths characteristic of substances existing in the examined location. Signals obtained by detecting from absorption at various wavelengths are processed by an electric circuit, so that quantitative data concerning the concentration of the substance to be measured is obtained without being influenced by the fluctuation of measuring conditions such as the fluctuation of the detector, the deviation of the intensity, the direction and angle of irradiation, and the fluctuation of the flow of blood in the examined location.
Further, British pat. No. 2,075,668 discloses a spectrophotometric apparatus for measuring and monitoring metabolic functions of an organism such as changes in oxidation and reduction of hemoglobins and cytochromes or changes in the blood flow in an organ such as the brain, heart, lever on an in vivo and in situ basis. The apparatus uses an irradiation light of wavelengths between 700 nm and 1,300 nm, which effectively penetrates several mm deep under skin.
FIG. 14 of the British patent application illustrates an apparatus for measuring reflectance comprising a wave guide (optical fiber tube) to be abutted to an organism and a light source. The wave guide is abutted to an organism so that irradiation light is applied to the surface of skin in an oblique direction, and the oriented irradiation light is made to penetrate into the body through skin and to be reflected or back-scattered from the tissue at a distance apart from the light source. Some of the light energy is absorbed and the rest is incident on a first detector placed on skin and apart from the light source. Also a second detector is placed and detects a backward-radiated reference signal. The analytical signal from the first detector and the reference signal from the second detector are output into an arithmetic operation circuit, and the data of analytical information is obtained as the output of the arithmetic operation circuit.
In measurement of the concentration of glucose and the like described above, the quality of the spectroscopic data obtained by a near-infrared spectrometer is determined by the performance of hardware constituting the near-infrared spectrometer. At present, the signal to noise ratio S/N of the best performance is approximately on the order between 10.sup.5 to 10.sup.6. On the other hand, for example, the prior methods of measuring the absolute intensity of the spectrum requires 10.sup.5 to 10.sup.6 order as the S/N ratio of the spectral signal to measure 100 mg/dL, which is the physiological concentration of glucose in blood, with spectroscopically practical precision, so that the measurement must be done near the maximum precision limit attainable by the spectrometer.
Therefore, methods of measuring the concentrations of sugar and glucose and the like using spectroscopic techniques have less sensitivity, precision and accuracy than chemical analysis that analyzes the concentrations of these substances using reagents, and a near-infrared spectrometer of high performance having a high S/N ratio is made with complex construction at great cost. Thus, if a variation of glucose concentration from the physiological concentration of glucose, 100 mg/dL, can be measured with the precision of 2 to 3 digits by a reference method, instead of simply measuring the absolute intensity of a spectrum, then we can find how much the blood sugar of a patient deviates from a normative value, so that the measurement can be favorably used for controlling the blood sugar of the patient.